5'-Methylthioadenosine (MTA) is a naturally occurring nucleoside enzymatically synthesized from S-adenosylmethionine by at least five pathways. In spite of these multiple routes of biosynthesis, MTA is present in only trace amounts in a variety of cells and tissues. We have demonstrated that MTA is a potent inhibitor of human lymphocytes stimulated to proliferate by a variety of antigens and mitogens. The effect of MTA is non-toxic, dose-dependent, and non-competitive with the stimulant. Resting cells are more sensitive to the inhibitory effect exerted by MTA than those cells which have already been stimulated. This is, most likely, due to the increased activity of MTA phosphorylase in activated lymphocytes. MTA phosphorylase activity also responds to hormonal stimulation in rat target tissues. In the continuation of this project, we intend 1) to document further the inhibitory effects of MTA and its analogues on cellular metabolism, 2) to elucidate the role of MTA in regulating macromolecule biosynthesis in vivo, and 3) to test the usefulness of MTA and its analogues as potential chemotherapeutic agents on rapidly dividing cells. To accomplish these goals we intend to investigate the synthesis, degradation, regulation, and potential inhibitory effects of MTA on a variety of rapidly dividing cells. Our understanding of the factors which effect MTA metabolism in these cells may lead to new approaches for regulating cellular proliferation.